Inflammatory pain is a very common clinical phenomenon that causes great individual suffering and expense to society. Some of the most severe forms of pain, particularly chronic inflammatory pains, are partly or wholly intractable to currently available therapies. The investigators have shown that the cAMP/PKA second messenger pathway plays a major role in hyperalgesia induced by prostaglandin E2 (PGE2) and recently that nitric oxide (NO) also contributes via a guanylyl cyclase-independent mechanism. They now propose to study the cellular mechanism(s) underlying an additional novel action of NO, guanylyl cyclase-dependent hyperalgesia. They will also investigate the role of PKCepsilon in hyperalgesia and nociceptor sensitization produced by other inflammatory mediators. The investigators will also study mechanisms of mechanical transduction in nociceptors. They have recently been able to demonstrate a mechanically-induced whole cell current in cultured dorsal root ganglion neurons. They propose to fully characterize this current in order to establish an in vitro electrophysiological model for the study of nociception of mechanical stimuli. The investigators will also investigate changes in second messenger pathways involved in chronic hyperalgesia, focusing on a novel phenomenon they recently discovered in which the hyperalgesic response to an inflammatory mediator is enhanced for a period of weeks following recovery from the inflammatory hyperalgesic state. These experiments should provide significant novel information about mechanisms of inflammatory pain and hyperalgesia and cellular mechanisms of mechanical transduction in primary afferent neurons that may be important in chronic pain states in humans. These investigations should yield insights into potential pharmacological targets for the treatment of chronic inflammatory pain.